This study will investigate the mechanisms of cannabinoid tolerance. This objective will be achieved by determining whether cannabinoid tolerance is mediated through agonist-specific mechanisms using a model of chemotherapy-induced neuropathic pain. Our approach will examine tolerance to the anti-allodynic and antinociceptive effects of ?9-THC, CP55,940, and WIN55,212-2, three cannabinoid agonists with distinct signaling and chemical features. Tolerance to ?9-THC antinociception in the tail-flick test was eliminated by pre-treatment of S426A/S430A mutants with SP600125, a selective c-Jun N-terminal kinase (JNK) inhibitor suggesting that JNK (SP600125 inhibitor) and GRK/?arrestin2 (S426/S430A mutation) signaling mechanisms coordinate to mediate tolerance to the antinociceptive effect of ?9-THC. The first objective of this study is to, fully and systematically, test the hypothesis that cannabinoid tolerance is mediated through agonist-specific mechanisms. The second objective is to test the hypothesis that JNK-mediated tolerance for ?9-THC requires the presence of ??arrestin2. The third objective is to test the hypothesis that ??arrestin2 and JNKs can form protein-protein interactions in vivo. The fourth objective is to test the hypothesis that JNKs can directly phosphorylate CB1 when activated by ?9-THC using a technologically innovative chemical-genetic approach. The first three hypotheses will be tested in a clinically relevant model of chemotherapy (cisplatin)-induced model of neuropathic pain. The last hypothesis is equally innovative and will provide important information regarding the molecular mechanism of action that is responsible for JNK-mediated ?9-THC tolerance. The overarching goal of this project is to gain a better understanding of the agonist-specific mechanisms responsible for cannabinoid tolerance that will facilitate the development of long lasting, highly efficacious, and personalized pain therapies.